Sjgren's syndrome (SS) is an autoimmune disease affecting more than 4 million Americans, over 90% of whom are women. SS is characterized by lymphocyte infiltration of lacrimal and salivary glands leading to dry eye and dry mouth, and resulting in severely compromised ocular surface and oral health. Some patients with SS also exhibit weight loss, fatigue, internal organ failure, and B-cell lymphoma. Despite its prevalence and severity, there are no approved therapies for treatment of SS. Treatments are based on management of ocular and oral dryness as well as use of general immunosuppressive drugs which are not optimized for the underlying autoimmune exocrinopathies. Although not developed for SS, RestasisTM, an ophthalmic emulsion of cyclosporine A approved for dry eye, has been explored for use in SS-mediated dry eye. While modestly effective in treating ocular surface symptoms, RestasisTM does not restore tear production. This is unsurprising because the nasolacrimal ducts efficiently drain drugs administered topically, limiting drug access to the lacrimal gland and to other sites of systemic inflammation. Systemic administration of cyclosporine A and rapamycin, another potent immunosuppressant, has been challenging because of their low solubility, poor bioavailability and dose-limiting toxicities. Surprisingly, no attempts have been made in SS to deliver these immunosuppressants to inflamed lacrimal or salivary glands using state-of-the-art drug carriers. Such a strategy could not only treat the origin of the severe ocular and oral cavity symptoms at their source, but also potentially mitigate the systemic and life-threatening complications of the disease. The goal of this project is to enhance the activity of these two clinically-approved immunosuppressants to treat inflamed lacrimal and salivary glands and other sites of disease activity in SS through use of an emerging class of `protein polymer' nanomedicines based on elastin-like polypeptides (ELPs) to develop untargeted and targeted drug carriers. Our preliminary studies show that rapamycin administered intravenously in a novel protein nanoparticle in a mouse model of SS reduced lacrimal gland inflammation and restored function, while suppressing the renal toxicity associated with free drug. We propose three SPECIFIC AIMS: 1) Optimize the route of administration of untargeted ELP drug carriers using murine models of SS; 2) Construct and evaluate molecularly-targeted immunosuppressive ELP nanoparticles using murine models of SS; and 3) Complete comparative pharmacokinetics and toxicology of optimal therapies for local and systemic SS. When successful, this translational project will produce a significant advance in drug delivery technology by generating protein-polymer nanoparticles decorated with proteins that specifically carry rapamycin and cyclosporine A, and can be targeted to sites of inflammation. Our experiments will lay the solid preclinical foundation justifying further investment in their clinical development as therapeutics for SS and other autoimmune diseases.